The proposed studies will analyze osteoclast generation and function in animals and humans with osteopetrosis. Osteoclast generation will be studied to elucidate: (1) the cell of origin, (2) the cellular microenvironment necessary to support generation, (3) the sequence of cellular events occurring in bone during osteoclast generation. The ability of calcitriol and heparin to stimulate normal and osteopetrotic bone resorption will be quantitated. Based on these results, therapy with these stimulants will be assessed in four osteopetrotic rodent mutants. These therapies will be compared to standard transplantation of marrow stem cells, as well as new transplantation techniques using enriched and/or stimulated stem cell populations. Assays will be devised to measure osteoclast generation and bone resorptive function in vitro. The clinical application of these assays will be tested. This knowledge base will be utilized to improve therapy for patients with osteopetrosis. The overall objective is to provide new therapies and assays which can be applied both to the treatment of patients with osteopetrosis, as well as to other metabolic bone diseases.